||Acute administration of caffeine, the most widely diffused psychostimulant drug, increases motor behavior, whereas continuous administration produces tolerance. In order to study whether, similar to other psychostimulant drugs, subchronic intermittent administration of caffeine induces sensitization of motor behavior and promotes cross-sensitization to amphetamine effects, rats were treated with caffeine (15 mg=kg i.p.) on alternate days for 14 days. Three days after discontinuation of treatment, a challenge of caffeine (15 mg=kg i.p.) or amphetamine (0.5, 1mg=kg s.c.) was given. Caffeine induced a sensitizedmotor behavioral response, associated with a decrease of adenosine A2A receptor and zif-268 mRNA levels in striatum and nucleus accumbens. Amphetamine administration produced a higher motor response in caffeine – than vehicle-pretreated rats, associated with a more pronounced increase of zif-268 mRNA levels in the medial striatum but not in the nucleus accumbens. The potentiation of amphetamine effects was not associated with modifications of amphetamine-induced dopamine release in nucleus accumbens in caffeine-pretreated rats compared to vehiclepretreated rats. The results demonstrate that intermittent pre-exposure to caffeine sensitizes the motor stimulant effects of both caffeine and amphetamine in rats. Sensitization to caffeine and cross-sensitization to amphetamine appear to be associated to post-synaptic neuroadaptive changes and to be related to the medial striatum rather than the nucleus accumbens.